1. Field of the Invention
This invention pertains to the field of mammalian nerve regeneration. More specifically, the present invention relates to a multi-layered, semi-permeable hollow conduit comprised of Type I collagen which conduit is used to promote nerve regeneration of a severed nerve so as to bridge a gap between the severed ends of said nerve. Methods of making the nerve regeneration conduit are also disclosed.
2. Discussion of Related Art
Since the first reported attempt at surgical nerve repair in the thirteenth century, the restoration of normal nerve function following nerve injury has remained a persistently elusive goal. It was believed that damage to nerves resulted in a permanent loss of all function due to the failure of the nerve tissue to regenerate. It was then learned that the regenerative capacities of both the peripheral nervous system and the central nervous system are considerable, if the appropriate conditions are provided. The search for the best "appropriate conditions" is ever ongoing since the basic mechanism of the factors controlling nerve regeneration still remain a mystery.
Many different approaches have been taken in an attempt to regenerate a nerve that has been subjected to trauma--be it a severed nerve or a nerve having a gap between its proximal and distal ends. One such technique involves the actual suturing of the proximal and distal ends of the severed nerve.
In spite of the evolution of the surgical microscope and a prodigious effort into refining techniques for accurate nerve approximation, the clinical results of surgical nerve repair are still disappointing. Scar tissue resulting from the surgical manipulations required for direct proximal-to-distal nerve suture frequently interferes with the growth of proximal stump axons into the distal nerve stump. If a substantial number of axons are prevented from crossing the anastomotic site, neuroma (painful nerve cell tumor) formation often results. As a result, prospects for acheiving significant reennervation are reduced. The end result is a lack of full return of motor and/or sensory function. Additionally, the regenerative potential of the damaged proximal nerve is frequently unpredictable and poorly understood.
Severe nerve injuries have required microsurgical grafting to span a defect. This technique involves surgically grafting a piece of a nerve from another part of the body. This approach too has limitations. The area from which the nerve was removed is left without sensation. Moreover, the amount of nerve tissue that can reasonably be removed for such grafts is also limited. However, suture techniques and/or grafting have not always been sufficient for repair of a severe defect. Still further, suture under tension, gap reduction by stretching, mobilization, flexion of a joint, or rerouting may compromise sensitive intraneuronal vascularity, and autografts induce a second surgical site with requisite risks and complications. Moreover, in many instances, there was either no nerve growth or only growth of connective tissue. Thus, the functional results of surgical repair of peripheral nerve injuries have been disappointing in spite of improved surgical techniques.
Strategies have been devised for allegedly enhancing the regeneration of peripheral nerves (those outside the spinal cord and brain). Thus, protection of the site of a neurorrhaphy from infiltration with fibrous tissue and prevention of neuromatous formation by the use of wrappers, cuffs, or tubes of various materials have been practiced since 1880. At that time, it was attempted to interpose a drain of decalcified bone between the severed ends of a sciatic nerve. Fibrous union without return of function, however, generally resulted. In addition to decalcified bone and vessels, fascia lata, fat, muscle, parchment, Cargile membrane, gelatin, agar, rubber, fibrin film, and various metals have been used with varying degrees of success. Many materials failed because they incited a foreign body reaction, produced constricting scar tissue, were technically difficult to apply, or required secondary operation for their removal.
Various enhancements in both entubulation and nerve wrapping have continued in order to facilitate nerve repair. Both resorbable and non-resorbable materials have been used to act as a channel to promote growth and regeneration in severed nerves which have been sutured together or in connection with nerve grafts.
More particularly, in "The Use of a Resorbable Wrapper for Peripheral-Nerve Repair" by David G. Kline, et al., (Journal of Neurosurgery, Vol XXI, No. 9, pp. 737-750, 1964), for example, collagen is used as a wrapping material around a severed nerve which had been sutured to insulate the site from surrounding connective tissue and to promote longitudinal orientation of the connective-tissue elements of the nerve to allegedly reduce axonal disorganization and restrict the tendency for regenerating axons to escape into extraneural tissue.
The use of a non-resorbable tube to aid in the alignment and joining of severed nerves is disclosed in U.S. Pat. No. 3,786,817. Here, the ends of a severed nerve are inserted into the ends of a tube until the nerve ends are close to each other or touch each other at the center of the tube. A fluid such as nitrogen is passed though the tube to aid in regeneration.
In U.S. Pat. No. 4,534,349, an absorbable hollow tubular device is provided which allegedly enables the sutureless repair of lacerated, severed, or grafted nerves wherein the device is comprised of a body-absorbable polymer.
In an article entitled "Fascicular Tubulization: A Cellular Approach to Peripheral Nerve Repair" by Joseph M. Rosen, et al., (Annals of Plastic Surgery, Vol. 11, No. 5, November, 1983), a cellular approach to nerve repair is discussed in which a polyglycolic acid tube is used around the fascicle as an artificial perineurium to separate fibrous healing from axonal regeneration until the perineurium reestablished its continuity across the repair site. The polyglycolic acid tube was resorbed without major cellular injury to the nerve. It was found that the longitudinal orientation of the repairs by fascicular tubulization was more organized than repairs simply made by suture but that the number of axon counts remained the same.
It has also been realized that the distal and proximal ends of a severed nerve need not be brought into abutting relationship with one another in order to have nerve regeneration. Instead of using a nerve graft, attempts have been made at bridging a gap within a nerve by inducing its growth over a considerable distance using various entubulation materials and techniques.
Both bioresorbable and non-resorbable materials have been used in tubes for bridging nerve gaps. For example, resorbable hollow polyester and polyester-composite channels for bridging gaps of between 5 to 9 mm in a mouse sciatic nerve within 6 to 12 weeks are disclosed in "Synthetic Bioresorbable Polymers: Polyester and Polyester-Composite Guidance Channels for Peripheral Nerve Repair" by E. Nyilas, et al., (Trans. Soc. Biomater., 6, 85, 1983).
In "Nerve Repair Using a Polyglactin Tube and Nerve Graft: An Experimental Study in the Rabbit" by Hakan Molander, et al. (Biomaterials, Vol. 4, pp. 276-280, October, 1983), a sectioned tibial nerve was bridged using a polyglactin mesh-tube and compared with a conventional nerve grafting in a rabbit. Only minor differences were observed in the results obtained between the two different techniques. The use of resorbable collagen tubes to bridge nerve gaps is discussed in "Nerve Regeneration Through Collagen Tubes" by W. Colin, et al., (Journal of Dental Research July, 1984, pp. 987-993).
Various anatomical parts have also been used as an aid to bridging nerve gaps. Thus, a comparison was made between nerves which were anastomosed by a conventional epineural suturing technique and nerves which were allowed to grow together without tension within a venous sleeve to which they were attached by traction and antirotation sutures, in an article entitled "Utilization of Venous Sleeves in Peripheral Nerve Repair" by N. Calteux, et al., (Ann. Chir. Main, 3 (2), 149-155, 1984). Neuroma formation was found to be reduced in the sheathed nerves as compared to the sutured nerves. Additionally, nerve conduction after 3 months was found to be somewhat greater in the sleeved anastomosis group.
So too, empty perineurial tubes have also been used as channels for bridging nerve gaps as disclosed in "Fascicular Nerve Graft Using An Empty Perineurial Tube: An Experimental Study in the Rabbit" by Y. Restrepo, et al., (Microsurgery 4: 105-112, 1983) and in "Empty Perineurial Tube Graft Used to Repair A Digital Nerve: A First Case Report" by Y. Restrepo, et al., (Microsurgery 6: 73-77, 1985).
More recently, in an effort to even further improve upon nerve regeneration, particularly across a gap, various regeneration promotion agents have been added to the interior of tubes in the form of a filling. Thus, rat sciatic nerve regeneration across a gap has been accomplished using a silicone tube packed with a protein, collagen, and a glycosaminoglycan polysaccharide and chondrotin-6-sulfate wherein these materials were cross-linked to form a porous network that is degradable by enzymes at rates that can be controlled during preparation, although the silicone tube itself is not biodegradable.
The use of a nerve guide made of a collagen matrix containing fibrinogen and fibronectin is disclosed in "Non-toxic Nerve Guide Tubes Support Neovascular Growth in Transected Rat Optic Nerve" by R. Madison, et al., (Experimental Neurology, 86(3): 448-461, 1984). The addition of these specific proteins to the inside of the nerve guide tube is said to have increased the amount of neovascular growth through the nerve guide lumens in the optic nerve.
By using a bioresorbable nerve guide filled with a laminin-containing gel, it was reported by Madison, et al. in "Increased Rate of Peripheral Nerve Regeneration Using Bioresorbable Nerve Guides and a Laminin-Containing Gel". (Experimental Neurology, 88: 767-772, 1985) that in vivo axonal regeneration in mice was hastened.
Although improved results in nerve regeneration have been obtained through the use of tubes filled with nerve regenerating promoters, there is still much room for further improvement. Particularly, the manufacture of tubes filled with such promoting agents is a relatively expensive and tedious process. Moreover, it would still be desirable to provide a means by which an even greater number of myelinated axons are regenerated, a faster rate of nerve growth is achieved, and longer nerve gaps are spanned. A need still exists to fulfill such a need and still reduce or eliminate problems that have been encountered with prior art nerve repair attempts such as revascularization, excessive fibrosis, reorientation of nerve fibres, and the final poor return of function of the end organs.